title: Ponatinib is a potent inhibitor of wild-type and drug-resistant gatekeeper mutant RET kinase.
abstract: RET kinase is aberrantly activated in thyroid cancers and in rare cases of lung and colon cancer, and has been validated as a molecular target in these tumors. Vandetanib was recently approved for the treatment of medullary thyroid cancer. However, vandetanib is ineffective in vitro against RET mutants carrying bulky aminoacids at position 804, the gatekeeper residue, similarly to drug-resistant BCR-ABL mutants in chronic myeloid leukemia. Ponatinib is a multi-target kinase inhibitor that was recently approved for treatment-refractory Philadelphia-positive leukemia. We show here potent inhibition of oncogenic RET by ponatinib, including the drug-insensitive V804M/L mutants. Ponatinib inhibited the growth of RET+ and BCR-ABL+ cells with similar potency, while not affecting RET-negative cells. Both in biochemical and in cellular assays ponatinib compared favorably with known RET inhibitors, such as vandetanib, cabozantinib, sorafenib, sunitinib and motesanib, used as reference compounds. We suggest that ponatinib should be considered for the treatment of RET+ tumors, in particular those expressing vandetanib-resistant V804M/L mutations.
authors.affiliation: Dept. of Health Sciences, University of Milano-Bicocca, via Cadore 48, 20900 Monza, Italy. luca.mologni@unimib.it
authors.forename: Luca
authors.initials: L
authors.lastname: Mologni
authors.forename: Sara
authors.initials: S
authors.lastname: Redaelli
authors.forename: Andrea
authors.initials: A
authors.lastname: Morandi
authors.forename: Ivan
authors.initials: I
authors.lastname: Plaza-Menacho
authors.forename: Carlo
authors.initials: C
authors.lastname: Gambacorti-Passerini
mesh_terms: D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics*; D057809:HEK293 Cells; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D050505:Mutant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051096:Proto-Oncogene Proteins c-ret / Q000037:antagonists & inhibitors* / Q000235:genetics*; D011724:Pyridazines / Q000494:pharmacology*
chemical_list: D007093:Imidazoles; D050505:Mutant Proteins; D047428:Protein Kinase Inhibitors; D011724:Pyridazines; C545373:ponatinib; D051096:Proto-Oncogene Proteins c-ret
keywords: ALL; CML; DMSO; FBS; FMTC; GDNF; Gatekeeper; MEN2; MTC; PTC; Ponatinib; RET; REarranged during Transfection; TKI; Thyroid cancer; Tyrosine kinase; acute lymphoblastic leukemia; chronic myeloid leukemia; dimethyl sulfoxide; familial MTC; fetal bovine serum; glial-derived neurotrophic factor; medullary thyroid carcinoma; multiple endocrine neoplasia type 2; papillary thyroid carcinoma; tyrosine kinase inhibitor